The Association Between Low Pregnancy-Associated Plasma Protein-A levels and Adverse Pregnancy Outcomes
Article Sidebar
Main Article Content
Abstract
Objective: The primary objective was to evaluate the association between low pregnancy-associated plasma protein-A (PAPP-A) levels and preterm birth. The secondary objectives included assessing the relationship between low PAPP-A levels and other adverse pregnancy outcomes, as well as analyzing factors affecting PAPP-A levels.
Materials and Methods: Medical records of all women with singleton pregnancies undergoing the combined first trimester Down syndrome screening test between 11-14 weeks of gestation from January 2014 to December 2023 were reviewed. Baseline characteristics and pregnancy outcomes, including miscarriage, stillbirth, gestational diabetes mellitus, gestational hypertension, preeclampsia, preterm delivery, and fetal growth restriction were compared between women with normal and low PAPP-A levels (< 0.4 multiples of median (MoM)).
Results: A total number of 2,023 women were enrolled, of whom 120 (5.9%) had low PAPP-A levels. Higher body mass index, multiparity, diabetes mellitus and hypertension negatively influenced PAPP-A levels. Women with low PAPP-A levels had significantly higher rates of preterm birth (15.8% vs 7.2%), gestational hypertension (12.5% vs 5.3%), and fetal growth restriction (10.8% vs 3.7%). At the 0.4 MoM cutoff, the sensitivity, specificity, NPV, and PPV for predicting preterm birth were 12.18%, 94.64%, 92.72%, and 16.10%, respectively. The area under the receiver operative characteristic curve was 0.597 for preterm birth, 0.578 for gestational hypertension, and 0.585 for fetal growth, respectively.
Conclusion: Low PAPP-A levels were significantly associated with preterm birth, gestational hypertension, and fetal growth restriction. However, the overall predictive performance was limited so PAPP-A should not be used as the sole indicator for clinical decision-making.
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
References
Fialova L, Malbohan IM. Pregnancy-associated plasma protein A (PAPP-A): theoretical and clinical aspects. Bratisl Lek Listy 2002;103:194–205.
Bischof P, DuBerg S, Herrmann W, Sizonenko PC. Pregnancy-associated plasma protein-A (PAPP-A) and hCG in early pregnancy. Br J Obstet Gynaecol 1981;88:973–5.
Zhang Z, Xu H, Liu X, Li P, Du W, Han Q. Association of pregnancy-associated plasma protein A and vascular endothelial growth factor with pregnancy-induced hypertension. Exp Ther Med 2019;18: 1761–7.
Patil M, Panchanadikar TM, Wagh G. Variation of PAPP-A level in the first trimester of pregnancy and its clinical outcome. J Obstet Gynaecol India 2014;64:116–9.
Costa SL, Proctor L, Dodd JM, Toal M, Okun N, Johnson JA, et al. Screening for placental insufficiency in high-risk pregnancies: is earlier better? Placenta 2008;29:1034–40.
Odibo AO, Patel KR, Spitalnik A, Odibo L, Huettner P. Placental pathology, first-trimester biomarkers and adverse pregnancy outcomes. J Perinatol 2014;34: 186–91.
Peterson SE, Simhan HN. First-trimester pregnancy-associated plasma protein A and subsequent abnormalities of fetal growth. Am J Obstet Gynecol 2008;198:e43–5.
Movahedi M, Khanjani S, Shahshahan Z, Hajihashemi M, Farahbod F, Shahsavandi E. Evaluation of the relationship between pregnancy-associated plasma protein A (PAPP-A) and pregnancy outcomes. Adv Biomed Res 2023;12:91.
Spencer K, Cowans NJ, Molina F, Kagan KO, Nicolaides KH. First-trimester ultrasound and biochemical markers of aneuploidy and the prediction of preterm or early preterm delivery. Ultrasound Obstet Gynecol 2008;31:147–52.
Kantomaa T, Vaarasmaki M, Gissler M, Sairanen M, Nevalainen J. First trimester low maternal serum pregnancy associated plasma protein-A (PAPP-A) as a screening method for adverse pregnancy outcomes. J Perinat Med 2023;51:500–9.
Luewan S, Teja-Intr M, Sirichotiyakul S, Tongsong T. Low maternal serum pregnancy-associated plasma protein-A as a risk factor of preeclampsia. Singapore Med J 2018;59:55–9.
Saxena AR, Seely EW, Rich-Edwards JW, Wilkins-Haug LE, Karumanchi SA, McElrath TF. First trimester PAPP-A levels correlate with sFlt-1 levels longitudinally in pregnant women with and without preeclampsia. BMC Pregnancy Childbirth 2013;13:85.
Papamichail M, Fasoulakis Z, Daskalakis G, Theodora M, Rodolakis A, Antsaklis P. Importance of low pregnancy associated plasma protein-A (PAPP-A) levels during the first trimester as a predicting factor for adverse pregnancy outcomes: A prospective cohort study of 2636 pregnant women. Cureus 2022;14:e31256.
Shah KH, Anjum A, Nair P, Bhat P, Bhat RG, Bhat S. Pregnancy associated plasma protein A: An indicator of adverse obstetric outcomes in a South India population. Turk J Obstet Gynecol 2020;17:40–5.
Pummara P, Tongsong T, Wanapirak C, Sirichotiyakul S, Luewan S. Association of first-trimester pregnancy-associated plasma protein A levels and idiopathic preterm delivery: A population-based screening study. Taiwan J Obstet Gynecol 2016;55:72–5.
D’Antonio F, Rijo C, Thilaganathan B, Akolekar R, Khalil A, Papageourgiou A, et al. Association between first-trimester maternal serum pregnancy-associated plasma protein-A and obstetric complications. Prenat Diagn 2013;33:839–47.
Brameld KJ, Dickinson JE, O’Leary P, Bower C, Goldblatt J, Hewitt B, et al. First trimester predictors of adverse pregnancy outcomes. Aust N Z J Obstet Gynaecol 2008;48:529–35.
Dane B, Dane C, Batmaz G, Ates S, Dansuk R. First trimester maternal serum pregnancy-associated plasma protein-A is a predictive factor for early preterm delivery in normotensive pregnancies. Gynecol Endocrinol 2013;29:592–5.
Goetzinger KR, Cahill AG, Macones GA, Odibo AO. Association of first-trimester low PAPP-A levels with preterm birth. Prenat Diagn 2010;30:309–13.
Tzanaki I, Makrigiannakis A, Lymperopoulou C, Al-Jazrawi Z, Agouridis AP. Pregnancy-associated plasma protein A (PAPP-A) as a first trimester serum biomarker for preeclampsia screening: a systematic review and meta-analysis. J Matern Fetal Neonatal Med 2025;38:2448502.
Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, Comstock CH, et al. First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial). Am J Obstet Gynecol 2004;191:1446–51.
Ong CY, Liao AW, Spencer K, Munim S, Nicolaides KH. First trimester maternal serum free beta human chorionic gonadotrophin and pregnancy associated plasma protein A as predictors of pregnancy complications. BJOG 2000;107:1265–70.
Choden N, Singh S, Chawla S. A study of the association of early pregnancy serum levels of pregnancy-associated plasma protein-A with adverse pregnancy outcome. Med J Dr DY Patil Vidyapeeth 2020;13:131.
Kazemi Aski S, Sharami SH, Tavangar A, Kazemnezhad E, Dalil Heirati SF, Etezadi A. Comparison of pregnancy-associated plasma protein-A levels in women with and without intrauterine growth restriction. J Obstet Gynecol Cancer Res 2024;9:14–21.
Lata I, Mishra P. Pregnancy-associated plasma protein A levels with pregnancy outcomes: A preliminary study. Thai J Obstet Gynaecol 2020;28:183–9.
Ranganathan A, Fresen J, Sarkar P. Association of low levels of first trimester pregnancy associated plasma protein (PAPP-A) with adverse pregnancy outcomes: An observational study. Obstet Gynecol Rep 2017;1:1-6.
Malone FD, Canick JA, Ball RH, Nyberg DA, Comstock CH, Bukowski R, et al. First-trimester or second-trimester screening, or both, for Down’s syndrome. N Engl J Med 2005;353:2001–11.
Mohamad Jafari R, Masihi S, Barati M, Maraghi E, Sheibani S, Sheikhvatan M. Value of pregnancy-associated plasma protein-A for predicting adverse pregnancy outcome. Arch Iran Med 2019;22:584–7.
Livrinova V, Petrov I, Samardziski I, Jovanovska V, Boshku AA, Todorovska I, et al. Clinical importance of low level of PAPP-A in first trimester of pregnancy - An obstetrical dilemma in chromosomally normal fetus. Open Access Maced J Med Sci 2019;7: 1475–9.
Lovati E, Beneventi F, Simonetta M, Laneri M, Quarleri L, Scudeller L, et al. Gestational diabetes mellitus: including serum pregnancy-associated plasma protein-A testing in the clinical management of primiparous women? A case-control study. Diabetes Res Clin Pract 2013;100:340–7.
Beneventi F, Simonetta M, Lovati E, Albonico G, Tinelli C, Locatelli E, et al. First trimester pregnancy-associated plasma protein-A in pregnancies complicated by subsequent gestational diabetes. Prenat Diagn 2011;31:523–8.
Petry CJ, Ong KK, Hughes IA, Acerini CL, Frystyk J, Dunger DB. Early pregnancy-associated plasma protein A concentrations are associated with third trimester insulin sensitivity. J Clin Endocrinol Metab 2017;102:2000–8.
Borna S, Ashrafzadeh M, Ghaemi M, Eshraghi N, Hivechi N, Hantoushzadeh S. Correlation between PAPP-A serum levels in the first trimester of pregnancy with the occurrence of gestational diabetes, a multicenter cohort study. BMC Pregnancy Childbirth 2023;23:847.
Wells G, Bleicher K, Han X, McShane M, Chan YF, Bartlett A, et al. Maternal diabetes, large-for-gestational-age births, and first trimester pregnancy-associated plasma protein-A. J Clin Endocrinol Metab 2015;100:2372–9.
Krantz DA, Hallahan TW, Macri VJ, Macri JN. Maternal weight and ethnic adjustment within a first-trimester Down syndrome and trisomy 18 screening program. Prenat Diagn 2005;25:635–40.
Spencer K, Bindra R, Nicolaides KH. Maternal weight correction of maternal serum PAPP-A and free beta-hCG MoM when screening for trisomy 21 in the first trimester of pregnancy. Prenat Diagn 2003;23:851–5.
Wright D, Silva M, Papadopoulos S, Wright A, Nicolaides KH. Serum pregnancy-associated plasma protein-A in the three trimesters of pregnancy: effects of maternal characteristics and medical history. Ultrasound Obstet Gynecol 2015;46:42–50.
Leung TY, Spencer K, Leung TN, Fung TY, Lau TK. Higher median levels of free beta-hCG and PAPP-A in the first trimester of pregnancy in a Chinese ethnic group. Implication for first trimester combined screening for Down’s syndrome in the Chinese population. Fetal Diagn Ther 2006;21:140–3.
Spencer K, Ong CY, Liao AW, Nicolaides KH. The influence of ethnic origin on first trimester biochemical markers of chromosomal abnormalities. Prenat Diagn 2000;20:491–4.
Luewan S, Sirichotiyakul S, Yanase Y, Traisrisilp K, Tongsong T. Median levels of serum biomarkers of fetal Down syndrome detected during the first trimester among pregnant Thai women. Int J Gynaecol Obstet 2012;117:140–3.
Manotaya S, Zitzler J, Li X, Wibowo N, Pham TM, Kang MS, et al. Effect of ethnicity on first trimester biomarkers for combined trisomy 21 screening: results from a multicenter study in six Asian countries. Prenat Diagn 2015;35:735–40.
Kor-Anantakul O, Suntharasaj T, Suwanrath C, Hanprasertpong T, Pranpanus S, Pruksanusak N, et al. Normative weight-adjusted models for the median levels of first trimester serum biomarkers for trisomy 21 screening in a specific ethnicity. PLoS One 2017;12:e0182538.
Regan L, Rai R, Saravelos S, Li TC. Recurrent miscarriage green-top guideline no. 17. BJOG 2023;130:e9-e39.
ACOG Practice Bulletin No. 102: Management of stillbirth. Obstet Gynecol 2009;113:748–61.
Metzger BE, Gabbe SG, Persson B, Buchanan TA, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676–82.
ACOG Practice Bulletin No. 190: Gestational dabetes mellitus. Obstet Gynecol 2018;131:e49–e64.
Gestational hypertension and preeclampsia: ACOG Practice Bulletin, Number 222. Obstet Gynecol 2020;135:e237–e60.
Fetal growth restriction: ACOG Practice Bulletin, Number 227. Obstet Gynecol 2021;137:e16–e28.
Hoffman MK. Prediction and prevention of spontaneous preterm birth: ACOG Practice Bulletin, Number 234. Obstet Gynecol 2021;138:945–6.
Safari S, Baratloo A, Elfil M, Negida A. Evidence based emergency medicine; Part 5 receiver operating curve and area under the curve. Emerg (Tehran) 2016;4: 111–3.
Ranta JK, Raatikainen K, Romppanen J, Pulkki K, Heinonen S. Decreased PAPP-A is associated with preeclampsia, premature delivery and small for gestational age infants but not with placental abruption. Eur J Obstet Gynecol Reprod Biol 2011;157:48–52.
Sun IY, Overgaard MT, Oxvig C, Giudice LC. Pregnancy-associated plasma protein A proteolytic activity is associated with the human placental trophoblast cell membrane. J Clin Endocrinol Metab 2002;87:5235–40.
